WT-161

WT-161 is a potent and selective HDAC6 inhibitor with an IC50 of 0.40 nM.

Research Areas >> Cancer

HDAC6:0.4 nM (IC50)

HDAC1:8.35 nM (IC50)

HDAC2:15.4 nM (IC50)

HDAC3:51.6 nM (IC50)

HDAC8:1430 nM (IC50)

WT161 selectively inhibits HDAC6 and dramatically increases levels of acetylated α-tubulin (Ac-α-tubulin) with little effect on global lysine acetylation. WT161 induces significant toxicity in all multiple myeloma cell lines tested, with IC50s between 1.5 and 4.7 µM . WT161 in combination with bortezomib triggers significant accumulation of polyubiquitinated proteins and cell stress, followed by caspase activation and apoptosis. More importantly, this combination treatment is effective in bortezomib-resistant cells and in the presence of bone marrow stromal cells, which have been shown to mediate multiple myeloma cell drug resistance[1].

WT161 shows toxicity at 100 mg/kg i.p., but WT161 is well tolerated at 50 mg/kg i.p.. Bortezomib combined with WT161 demonstrates a significant antitumor effect[1].

MM.1S cells are treated with increasing concentrations of WT161 (0-10 μM) for 48 hours. Cell viability is determined using the MTT assay[1].

Mice: Mice tumor xenograft are assigned into cohorts receiving vehicle (control), BTZ (0.5 mg/kg, i.v.), WT161 (50 mg/kg, i.p.), or BTZ+WT161. WT161 is administered for five consecutive days each week, and BTZ is given on a twice-weekly schedule. Caliper measurements of the longest perpendicular tumor diameters are performed on alternate days to estimate the tumor volume[1].

[1]. Hideshima T, et al. Discovery of selective small-molecule HDAC6 inhibitor for overcoming proteasome inhibitor resistance in multiple myeloma. Proc Natl Acad Sci U S A. 2016 Nov 15;113(46):13162-13167.

Trichostatin A | Entinostat (MS-275) | Romidepsin (FK228, Depsipeptide) | Mocetinostat(MGCD0103) | Ricolinostat (ACY-1215) | Sodium butyrate | RGFP 966 | Quisinostat | Tubacin | DL-Sulforaphane | CUDC-907 | LMK 235 | CI-994 | Tubastatin A | Sodium phenylbutyrate